Introduction of Heteroaromatic Bases onto Cycloalkanes with BPO

Article abstract of DOI:10.1002/ejoc.201801797

Heteroaromatic bases, such as lepidine, phenanthridine, isoquinoline, etc., were treated with cycloalkanes, such as cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc., under warming conditions with benzoyl peroxide (BPO) to form heteroaromatic bases bearing cycloalkyl groups in good yields. Here, the inert C(sp³)-H bond of cycloalkanes could be functionalized to C(sp³)-heteroaromatic bases via an oxidative radical reaction pathway under transition-metal-free conditions.

Full text of DOI:10.1002/ejoc.201801797

DOI: 10.1002/ejoc.201801797
Full Paper
Heteroaromatic Bases
Introduction of Heteroaromatic Bases onto Cycloalkanes with
BPO
Luan Zhou[a] and Hideo Togo*[a]
Abstract: Heteroaromatic bases, such as lepidine, phen- form heteroaromatic bases bearing cycloalkyl groups in good
anthridine, isoquinoline, etc., were treated with cycloalkanes, yields. Here, the inert C(sp3)-H bond of cycloalkanes could be
such as cyclopentane, cyclohexane, cycloheptane, cyclooctane, functionalized to C(sp3)-heteroaromatic bases via an oxidative
etc., under warming conditions with benzoyl peroxide (BPO) to radical reaction pathway under transition-metal-free conditions.
Introduction
centered radicals has been well established.[2] In particular, the
introduction of alkyl groups onto nitrogen-containing hetero-
aromatic bases, such as quinoline, isoquinoline, etc., using aq.
H2O2 with Fe2+ (Fenton system); aq. H2O2 with Ti3+; tBuOOH
with Fe2+; (NH4)2S2O8 with Fe2+or Ti3+ in alcohol, dioxane, or
THF; N-chloroamine with Fe2+ in alkane; alkyl iodide with
benzoyl peroxide (BPO) and Fe3+; and (NH4)2S2O8 with Ag+ in
ether or alcohol has been well studied particularly by Minisci.[3]
As more typical and practical methods for the introduction of
alkyl groups onto nitrogen-containing heteroaromatic bases,
the decarboxylative alkylation of electron-deficient nitrogen-
containing heteroaromatic bases using aliphatic carboxylic ac-
ids with Na2S2O8 in the presence of AgNO3,[4] using N-acyloxy-
2-thiopyridone prepared from carboxylic acids and N-hydroxy-
2-thiopyridone under irradiation with a tungsten lamp,[5] and
using alkyl bromides with (Me3Si)3SiH or (Ph2SiH)2 in the pres-
ence of AIBN[6] was reported. The introduction of a cyclohexyl
group onto nitrogen-containing heteroaromatics using O-cyclo-
hexyl S-methyl dithiocarbonate and BPO was also reported.[7]
We have also reported the introduction of heteroaromatic bases
onto ether and cyclic ether using heteroaromatic bases and
BPO in ethers or cyclic ethers at 80 °C,[8a] the introduction of
heteroaromatic bases onto tertiary or secondary amide groups
using BPO in tertiary or secondary amides under irradiation
with a high-pressure mercury lamp,[8b] and the introduction of
heteroaromatic bases onto methanol using heteroaromatic
bases and Na2S2O8 in a mixture of methanol and water at
70 °C.[8c]
Nitrogen-containing heteroaromatic bases, such as quinoline
and isoquinoline, are one of the most important heteroaromat-
ics because most of them have biological activities. Natural
products containing a quinoline or an isoquinoline unit, such
as quinine, chloroquine, camptothecin, and palmatine, are
shown in Figure 1.[1] On the other hand, saturated hydro-
carbons are chemically inert to most reagents and rather hydro-
phobic. Therefore, the introduction of nitrogen-containing
heteroaromatic bases onto inert and hydrophobic cycloalkanes
is an attractive idea. However, the introduction of nitrogen-con-
taining heteroaromatic bases onto cycloalkanes is not easy be-
cause cycloalkanes are inert to most chemical reagents except
halogen atoms, such as fluorine, chlorine, and bromine atoms.
Figure 1. Natural products bearing quinoline or isoquinoline units.
On the other hand, the introduction of functional groups,
such as heteroaromatic bases, onto cycloalkanes in the pres-
ence of Pd(OAc)2, Cu(OTf)2, FeCl2, or other transition metals has
been actively studied.[9] Recent reports for the introduction of
heteroaromatic bases onto cycloalkanes via radical reaction
pathways are as follows; the introduction of heteroaromatic
bases onto cycloalkanes with K2S2O8 in the presence of TBADT
[(Bu4N)4(W10O32)] under irradiation with a Xe lamp at 40 °C;[10a]
the introduction of purine nucleosides onto cycloalkanes with
DTBP at 140 °C;[10b] and the introduction of 4,7-dichloro-
quinoline onto cycloalkanes and alkanes with PhI(O2CCF3)2 and
Today, the introduction of alkyl groups derived from carb-
oxylic acids, alcohols, alkyl halides, and ethers, etc., onto nitro-
gen-containing heteroaromatic bases that are activated by pro-
tonation with acids, such as trifluoroacetic acid and p-toluene-
sulfonic acid, etc., via the formation of nucleophilic carbon-
[a] Graduate School of Science, Chiba University, Yayoi-cho 1-33,
Inage-ku, Chiba 263-8522 Japan
E-mail: togo@faculty.chiba-u.jp
http://reaction-2.chem.chiba-u.jp/index.html
Supporting information for this article is available on the WWW under
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NaN3 at room temperature.[10c] Among them, the introduction (5.0 mL) and DCE (1.0 mL) at 100 °C for 4 h was best, giving
of heteroaromatic bases onto inert hydrocarbons, such as cyclo- compound 2a-B in 89 % yield (entry 14).
alkanes, under transition-metal-free conditions[10b,10c] is very at-
tractive, although it requires a high temperature[10b] or toxic
Table 1. Introduction of lepidine 1a onto cyclohexane.
reagents.[10c] As far as we know, studies for the introduction of
heteroaromatic bases onto cycloalkanes under transition-metal-
free and mild conditions are limited. The reaction of lepidine
(4-methylquinoline) and 2-methylquinoline with BPO in cyclo-
hexane was reported.[11] However, the substrates were limited
to the reactions of lepidine and isoquinoline with BPO in cyclo-
hexane or cyclooctane, and the yields were dependent on the
substrates.[11] Therefore, the generality and synthetic utility for
the introduction of heteroaromatic bases onto cycloalkanes
with BPO, and the study for utility of other oxidants are re-
quired.
As part of our synthetic studies for the introduction of
heteroaromatic bases onto ethers, amides, and methanol,[8]
here we would like to report a simple introduction of heteroaro-
matic bases onto cycloalkanes using BPO in cycloalkanes under
transition-metal-free and irradiation-free conditions.
Results and Discussion
Initially, screening experiments of oxidants for the introduction
of lepidine 1a onto cyclohexane were carried out, as shown in
Table 1. A mixture of lepidine 1a (2 mmol), trifluoroacetic acid
(1.3 equiv., TFA), and oxidant (1.3 equiv.), such as K2S2O8 (98 %
purity), Na2S2O8 (97 % purity), aq. H2O2 (30 % purity), tBuOOH
(70 % purity, TBHP), (tBuO)2 (94 % purity, DTBP), m-chloroper-
oxybenzoic acid (70 % purity, mCPBA), and BPO (75 % purity),
[a] Yield of recovered lepidine 1a. [b] Without DCE. [c] Reaction was carried
out under irradiation with Hg-lamp (400 W). [d] Without Brønsted acid.
As a gram-scale experiment, treatment of lepidine 1a
in cyclohexane (B, 5 mL) and 1,2-dichloroethane (DCE, 1 mL) in (10.0 mmol) under the same procedure and conditions in a
a 30 mL screw-capped flask was warmed at 80 °C for 4 h to 100 mL screw-capped flask provided compound 2a-B in 85 %
give 2-cyclohexy-4-methylquinoline 2a-B in 27 %, 29 %, 0 %, yield, as shown in Scheme 1. Based on those results, lepidine
0 %, 18 %, 0 %, and 85 % yields, respectively (entries 1–7). BPO 1a was treated with BPO (1.3 equiv.) and CF3CO2H (1.3 equiv.) in
showed the best reactivity among those oxidants to give com- a mixture of cyclopentane (A, 5.0 mL), cycloheptane (C, 5.0 mL),
pound 2a-B in 85 % yield (entry 7). When the solvent ratio of cyclooctane (D, 5.0 mL), and cyclododecane (E, 5.0 mL) with
cyclohexane and DCE was changed to 6:0 (6.0 mL), 5:0.5 DCE (1.0 mL), respectively, and adamantane (F, 5.0 equiv.) with
(5.5 mL), 4:2 (6.0 mL), and 3:3 (6.0 mL) using the same condi- benzene (4.0 mL), at 100 °C for 4 h to provide 2-cycloalkyl-4-
tions as in entry 7, the yields of 2a-B were decreased as com- methylquinolines 2a-A, 2a-C–2a-F in good yields, respectively,
pared with that in entry 7 (5:1, 6.0 mL) (entries 8–11). When the as shown in Scheme 1. The same treatment of 6-methoxy-2-
reaction temperature was changed to 70 °C, 90 °C, and 100 °C methylquinoline 1b with BPO and CF3CO2H in a mixture of
using the same conditions as in entry 7, the reaction at cyclopentane, cyclohexane, cycloheptane, cyclooctane, or
100 °C showed the best result to give compound 2a-B in 89 % cyclododecane (5.0 mL) and DCE (1.0 mL), at 100 °C for 4 h
yield (entries 7 and 12–14). When the reaction time was gave 4-cycloalkyl-6-methoxy-2-methylquinolines 2b-A–2b-E in
changed to 5 h and 24 h using the same conditions as in entry good yields again, respectively, as shown in Scheme 1. When
14, the yield of compound 2a-B was almost the same (entries 2-methylquinoline 1c, 2-chloroquinoline 1d, and 7-chloro-2-
15 and 16). Furthermore, when the present reaction was carried methylquinoline 1e were treated with BPO and CF3CO2H in cy-
out under irradiation with a mercury lamp (400 W, high-pres- clohexane under the same conditions, 4-cyclohexyl-2-methyl-
sure lamp) at 30–40 °C for 24 h, instead of warming at 100 °C quinoline 2c-B, 2-chloro-4-cyclohexylquinoline 2d-B, and 7-
for 4 h, compound 2a-B was again obtained in 86 % yield (entry chloro-4-cyclohexyl-2-methylquinoline 2e-B were also obtained
17). When the present reaction was carried out with pTsOH·H2O in good yields, respectively. On the other hand, treatment of
and CH3SO3H instead of CF3CO2H using the best conditions in quinoline 1f in cyclohexane under the same conditions gave a
entry 14, the yield of compound 2a-B was decreased to 62 % mixture of 2-cyclohexylquinoline, 4-cyclohexylquinoline, and
and 51 %, respectively (entries 18 and 19), and in the absence 2,4-dicyclohexylquinoline in 80 % yield with almost the same
of an acid, the yield of compound 2a-B was markedly de- ratio. The selective introduction of a cyclohexyl group to 2-posi-
creased to 21 % (entry 20). Thus, the warming treatment of tion or 4-position of quinoline 1f was impossible even if the
lepidine 1a with BPO (1.3 equiv.) in a mixture of cyclohexane amount of BPO and the reaction time were changed. Warming
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treatment of quinoline 1f with BPO (3.0 equiv.) in cyclohexane
(5.0 mL) and DCE (1.0 mL) at 100 °C for 4 h gave 2,4-dicyclohex-
ylquinoline 2f-B in 63 % yield.
Then, phenanthridine 1g was treated with BPO and CF3CO2H
in cyclopentane, cyclohexane, cycloheptane, cyclooctane, and
cyclododecane with DCE (1.0 mL), respectively, and adamant-
ane (5.0 equiv.) with benzene (4.0 mL), at 100 °C for 4 h to
provide 6-cycloalkylphenanthridines 2g-A–2g-F in good yields,
respectively, as shown in Scheme 1. When isoquinoline 1h and
benzothiazole 1j were treated with BPO and CF3CO2H in cyclo-
pentane, cyclohexane, cycloheptane, cyclooctane, and cyclodo-
decane with DCE (1.0 mL), respectively, and adamantane
(5.0 equiv.) with benzene (4.0 mL), at 100 °C for 4 h, 1-cyclo-
alkylisoquinolines 2h-A–2h-F and 2-cycloalkylbenzothiazoles
2j-A–2j-F were generated in good yields, respectively. 4-
Bromoisoquinoline 1i in cyclohexane could be also converted
into 4-bromo-1-cyclohexylisoquinoline 2i-B in 94 % yield under
the same conditions.
As regards the synthetic use of the present reaction prod-
ucts, 2-cyclohexyl-4-methylquinoline 2a-B (1.0 mmol), 6-cyclo-
hexylphenanthridine 2g-B (1.0 mmol), and 1-cyclohexylisoquin-
oline 2h-B (1.0 mmol) were treated with N-bromosuccinimide
(NBS, 1.5 equiv.) in CCl4 (4.0 mL) under irradiation with a tung-
sten lamp (300 W) to form brominated compounds 3a-B, 3g-B,
and 3h-B in good yields, respectively, using the Wohl-Ziegler
reaction. Further treatment of brominated compounds 3a-B,
3g-B, and 3h-B with tBuOK in THF at room temperature gener-
ated 1-cyclohexenyl derivatives 4a-B, 4g-B, and 4h-B in 67 %,
Scheme 2. Transformation of the cyclohexyl group to cyclohexenyl and
phenyl groups.
Scheme 1. Introduction of heteroaromatic bases 1 onto cycloalkanes.
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62 %, and 64 % yields from cyclohexyl compounds 2a-B, 2g-B, Experimental Section
and 2h-B, respectively, as shown in Scheme 2.
1
General: H-NMR spectra were measured on 400 MHz spectrome-
ters. Chemical shifts were recorded as follows: chemical shift in ppm
from internal tetramethylsilane on the δ scale, multiplicity (s = sin-
glet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad),
coupling constant (Hz), integration, and assignment. 13C-NMR spec-
tra were measured on 100 MHz spectrometers. Chemical shifts were
recorded in ppm from the solvent resonance employed as the inter-
nal standard (deuterochloroform at 77.0 ppm). Characteristic peaks
Further treatment of 1-cyclohexenyl derivatives 4a-B, 4g-B,
and 4h-B with SeO2 at 80 °C in DCE gave 4-methyl-2-phenyl-
quinoline 5a-B, 6-phenylphenanthridine 5g-B, and 1-phenyliso-
quinoline 5h-B in moderate yields, respectively, as shown in
Scheme 2.
When the reaction of lepidine (1a, 2.0 mmol) with BPO
(1.3 equiv.) and CF3CO2H (1.3 equiv.) in a mixture of cyclohex-
ane (5.0 mL) and DCE (1.0 mL) at 100 °C for 4 h was carried out
in the presence of 2,6-di-tert-butyl-p-cresol (BHT, 2.6 equiv.) and
2,2,6,6-tetramethylpiperidine-1-oxy radical (TEMPO, 2.6 equiv.)
under the same conditions, the yields of 2-cyclohexyl-4-methyl-
quinoline 2a-B were 0 % and 1 %, and lepidine 1a was recov-
ered in 89 % and 93 % yields, respectively. Based on those re-
sults, a possible reaction mechanism for the introduction of het-
eroaromatic bases 1 onto cycloalkanes (A–F) with BPO is shown
in Scheme 3.
in the infrared (IR) spectra were recorded in wave number, cm–1
.
High-resolution mass spectra were recorded by Thermo Fisher Sci-
entific Exactive Orbitrap mass spectrometers. Melting points were
uncorrected. The products were purified by column chromatogra-
phy on neutral silica gel 60N (63–210 mesh).
Typical Procedure for Introduction of Heteroaromatic Bases 1 onto
Cycloalkanes with BPO; Preparation of 2-Cyclohexyl-4-methyl-
quinoline: BPO (2.6 mmol, 839.7 mg) and CF3CO2H (2.6 mmol,
0.3 mL) were added to a solution of lepidine (1a; 2.0 mmol,
286.4 mg) in a mixture of cyclohexane and DCE (5:1; 6.0 mL) in a
screw-capped flask (30 mL) at room temperature. The mixture was
flushed with argon gas, and was stirred for 4 h at 100 °C. The reac-
tion mixture was then cooled to room temperature, and the solvent
was removed under reduced pressure. Then, the residual mixture
was quenched with satd. aq. NaHCO3 (10 mL) and was extracted
with CHCl3 (3 × 20 mL). The resulting organic layer was dried with
Na2SO4, and filtered, and the solvent was removed under reduced
pressure. The residue was purified by column chromatography on
neutral silica gel (eluent: EtOAc/hexane, 1:15) to give product 2a-
B (401.1 mg, 89 %).
2-Cyclopentyl-4-methylquinoline (2a-A): 350.8 mg, 80 % yield;
yellow oil; IR (neat) 2950, 2866, 1176, 1033, 521 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 1.71–1.92 (m, 6H), 2.13–2.20 (m, 2H), 2.68 (s,
3H), 3.33 (quin, J = 8.6 Hz, 1H), 7.18 (s, 1H), 7.49 (td, J1 = 7.7 Hz, J2 =
1.3 Hz, 1H), 7.66 (td, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 7.94 (dd, J1 =
7.7 Hz, J2 = 1.3 Hz, 1H), 8.03 (d, J = 7.7 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 18.8, 26.0, 33.6, 48.8, 120.6, 123.5, 125.3, 126.9,
Scheme 3. Possible reaction pathway.
128.9, 129.4, 144.0, 147.5, 165.9 ppm; HRMS (ESI) calcd for C15H18
N
[M + H]+ 212.1434, found 212.1434.
Benzenecarboxyl radical formed from BPO under warming
conditions abstracts a hydrogen atom from cycloalkane to form
cycloalkyl radical and benzoic acid. Once the cycloalkyl radical
is formed, it reacts smoothly with a protonated heteroaromatic
base via nucleophilic radical interaction to form an adduct
which is further oxidized by a benzenecarboxyl radical to form
a protonated heteroaromatic base bearing a cycloalkyl group
and benzoic acid. After quenching with aq. NaHCO3, heteroaro-
matic base bearing cycloalkyl group 2 is obtained.
2-Cyclohexyl-4-methylquinoline (2a-B): 401.1 mg, 89 % yield; yel-
low oil; IR (neat) 2923, 2850, 1340, 1172, 535 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 1.20–2.08 (m, 10H), 2.68 (s, 3H), 2.87 (tt, J1 =
12.0 Hz, J2 = 3.4 Hz, 1H), 7.17 (s, 1H), 7.49 (td, J1 = 7.7 Hz, J2 = 1.3 Hz,
1H), 7.66 (td, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 7.94 (dd, J1 = 7.7 Hz, J2 =
1.3 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 18.8, 26.1, 26.5, 32.8, 47.6, 120.2, 123.5, 125.3, 127.0, 128.9, 129.4,
144.2, 147.5, 166.5 ppm; HRMS (ESI) calcd for C16H20N [M + H]+
226.1590, found 226.1587.
2-Cycloheptyl-4-methylquinoline (2a-C): 454.8 mg, 95 % yield;
yellow oil; IR (neat) 2920, 2852, 1412, 1178, 580 cm–1 1H NMR
;
Conclusions
(400 MHz, CDCl3) δ 1.59–1.90 (m, 10H), 2.01–2.06 (m, 2H), 2.68 (s,
3H), 3.03 (tt, J1 = 11.0 Hz, J2 = 3.4 Hz, 1H), 7.13 (s, 1H), 7.49 (td, J1 =
7.7 Hz, J2 = 1.3 Hz, 1H), 7.66 (td, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 7.93
(dd, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 18.8, 27.4, 27.9, 35.0, 49.6, 120.2, 123.5,
125.3, 127.0, 128.9, 129.4, 144.3, 147.3, 168.1 ppm; HRMS (ESI) calcd
for C17H22N [M + H]+ 240.1747, found 240.1742.
Heteroaromatic bases, such as lepidine, phenanthridine, and
isoquinoline, could be smoothly introduced onto inert cyclo-
alkanes, such as cyclopentane, cyclohexane, cycloheptane, and
cyclooctane, to form heteroaromatic bases bearing cycloalkyl
groups by treatment with BPO in cycloalkanes. The present
method would be useful for the preparation of heteroaromatic
bases bearing cycloalkyl groups, as warming of the reaction
mixture at 100 °C for 4 h with BPO generates heteroaromatic
bases bearing cycloalkyl groups under transition-metal-free
conditions, and scale-up preparation is easy.
2-Cyclooctyl-4-methylquinoline (2a-D): 420.6 mg, 83 % yield; yel-
low oil; IR (neat) 2917, 2848, 1507, 1171, 519 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 1.62–1.74 (m, 8H), 1.84–2.02 (m, 6H), 2.68 (s,
3H), 3.11 (tt, J1 = 12.0 Hz, J2 = 3.6 Hz, 1H), 7.12 (s, 1H), 7.49 (td, J1 =
7.7 Hz, J2 = 1.3 Hz, 1H), 7.66 (td, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 7.93
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(dd, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 8.04 (d, J = 7.7 Hz, 1H) ppm; 13
NMR (100 MHz, CDCl3) δ 18.8, 26.1, 26.3, 26.5, 33.5, 47.5, 120.6,
C
(quin, J = 6.0 Hz, 1H), 3.94 (s, 3H), 7.14 (s, 1H), 7.31–7.34 (m, 2H),
7.94 (dd, J1 = 9.1 Hz, J2 = 2.7 Hz, 1H) ppm; 13C NMR (100 MHz,
123.5, 125.2, 126.8, 128.8, 129.4, 144.2, 147.3, 168.8 ppm; HRMS (ESI) CDCl3) δ 22.4, 23.4(2C), 23.7, 23.9, 25.2, 29.7, 34.1, 55.3, 101.5, 119.5,
calcd for C18H24N [M + H]+ 254.1903, found 254.1897.
120.6, 126.4, 130.8, 144.0, 151.5, 155.9, 156.8 ppm; HRMS (ESI) calcd
for C23H34ON [M + H]+ 340.2635, found 340.2623.
2-Cyclododecyl-4-methylquinoline (2a-E): 482.8 mg, 78 % yield;
white soild, mp 90–91 °C; IR (neat) 2926, 2859, 1510, 1414,
862 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.29–1.60 (m, 18H), 1.67–1.76
(m, 2H), 1.86–1.95 (m, 2H), 2.68 (s, 3H), 3.09 (quin, J = 6.8Hz, 1H),
7.13 (s, 1H), 7.49 (td, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 7.66 (td, J1 = 7.7 Hz,
J2 = 1.3 Hz, 1H), 7.94 (dd, J1 = 7.7 Hz, J2 = 1.3 Hz, 1H), 8.06 (d, J =
7.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 18.8, 22.8, 23.3, 23.6,
23.8, 23.9, 30.1, 43.0, 121.3, 123.5, 125.2, 126.9, 128.7, 129.6, 143.7,
147.6, 166.7 ppm; HRMS (ESI) calcd for C22H32N [M + H]+ 310.2529,
found 310.2516.
4-Cyclohexyl-2-methylquinoline (2c-B): 347.0 mg, 77 % yield; yel-
low oil; IR (neat) 2925, 2851, 1196, 1131, 894 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 1.25–1.41 (m, 2H), 1.48–1.61 (m, 4H), 1.84–2.05
(m, 4H), 2.72 (s, 3H), 3.28–3.32 (m, 1H), 7.17 (s, 1H), 7.49 (td, J1 =
7.6 Hz, J2 = 1.1 Hz, 1H), 7.65 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 8.02
(d, J = 7.6 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 25.5, 26.3, 26.9, 33.5, 38.7, 118.3, 122.8, 125.1, 125.2, 128.7,
129.5, 148.1, 153.3, 158.8 ppm; HRMS (ESI) calcd for C16H20N [M +
H]+ 226.1590, found 226.1578.
2-(Adamantan-1′-yl)-4-methylquinoline (2a-F): 416.1 mg, 75 %
2-Chloro-4-cyclohexylquinoline (2d-B): 346.1 mg, 71 % yield;
yield; white soild, mp 122–123 °C; IR (neat) 2900, 2846, 2360, 817,
white soild, mp 214–215 °C; IR (neat) 2926, 2850, 1509, 1038,
1
536 cm–1; H NMR (400 MHz, CDCl3) δ 1.59–1.63 (m, 3H), 1.74–1.83
1
990 cm–1; H NMR (400 MHz, CDCl3) δ 1.24–1.61 (m, 5H), 1.82–2.05
(m, 4H), 1.95–2.06 (m, 2H), 2.11–2.17 (m, 6H), 2.69 (s, 3H), 7.33 (s,
1H), 7.47–7.52 (m, 1H), 7.63–7.68 (m, 1H), 7.92–7.96 (m, 1H), 8.04–
8.07 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 19.0, 28.0, 28.8, 30.9,
32.6, 36.9, 37.9, 39.1, 39.5, 41.8, 50.3, 118.5, 123.4, 125.3, 126.7,
(m, 5H), 3.00–3.07 (m, 1H), 6.62 (s, 1H), 7.24 (td, J1 = 7.6 Hz, J2 =
1.1 Hz, 1H), 7.39 (d, J = 7.0 Hz, 1H), 7.50 (td, J1 = 7.6 Hz, J2 = 1.1 Hz,
1H), 7.78 (d, J = 7.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 26.2,
26.8, 33.0, 39.1, 116.9, 117.0, 119.3, 122.4, 123.7, 130.2, 138.6, 158.1,
164.7 ppm; HRMS (ESI) calcd for C15H17NCl [M + H]+ 246.1044, found
246.1051.
128.6, 129.8, 143.6, 147.5, 168.7 ppm; HRMS (ESI) calcd for C20H24
N
[M + H]+ 278.1903, found 278.1891.
4-Cyclopentyl-6-methoxy-2-methylquinoline (2b-A): 415.0 mg,
86 % yield; yellow oil; IR (neat) 2952, 2869, 1562, 1119, 927 cm–1
7-Chloro-4-cyclohexyl-2-methylquinoline (2e-B): 374.1 mg, 72 %
1
yield; yellow oil; IR (neat) 2926, 2852, 1191, 649, 504 cm–1; H NMR
;
1H NMR (400 MHz, CDCl3) δ 1.70–1.92 (m, 6H), 2.16–2.25 (m, 2H),
2.68 (s, 3H), 3.64 (quin, J1 = 8.3 Hz, 1H), 3.94 (s, 3H), 7.16 (s, 1H),
7.31 (s, 1H), 7.34 (dd, J1 = 9.1 Hz, J2 = 2.7 Hz, 1H), 7.94 (d, J = 9.1 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 25.0, 25.3, 32.8, 40.5, 55.3,
102.3, 118.0, 120.4, 126.6, 130.5, 143.8, 150.7, 156.0, 156.7 ppm;
HRMS (ESI) calcd for C16H20ON [M + H]+ 242.1539, found 242.1532.
(400 MHz, CDCl3) δ 1.24–1.41 (m, 1H), 1.47–1.60 (m, 4H), 1.84–2.05
(m, 5H), 2.70 (s, 3H), 3.21–3.26 (m, 1H), 7.16 (s, 1H), 7.43 (dd, J1 =
9.0 Hz, J2 = 2.2 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 8.02 (d, J = 2.3 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 25.5, 26.2, 26.8, 33.4, 38.8,
118.5, 123.5, 124.2, 126.0, 128.4, 134.5, 148.6, 153.3, 160.0 ppm;
HRMS (ESI) calcd for C16H19NCl [M + H]+ 260.1201, found 260.1195.
4-Cyclohexyl-6-methoxy-2-methylquinoline (2b-B): 413.7 mg,
2,4-Dicyclohexylquinoline (2f-B): 369.7 mg, 63 % yield; yellow oil;
1
81 % yield; yellow oil; IR (neat) 2926, 2851, 1119, 921, 549 cm–1; H
1
IR (neat) 2923, 2850, 990, 616, 509 cm–1; H NMR (400 MHz, CDCl3)
NMR (400 MHz, CDCl3) δ 1.24–1.61 (m, 5H), 1.84–2.05 (m, 5H), 2.68
(s, 3H), 3.15–3.20 (m, 1H), 3.95 (s, 3H), 7.13 (s, 1H), 7.28 (d, J = 2.7 Hz,
1H), 7.33 (dd, J1 = 9.1 Hz, J2 = 2.7 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 25.0, 26.2, 26.8, 33.2, 38.9, 55.3,
101.8, 118.4, 120.2, 125.7, 130.7, 143.8, 151.8, 156.1, 156.8 ppm;
HRMS (ESI) calcd for C17H22ON [M + H]+ 256.1696, found 256.1690.
δ 1.24–1.69 (m, 10H), 1.77–2.05 (m, 10H), 2.88 (tt, J1 = 12.0 Hz, J2 =
3.4 Hz, 1H), 3.27–3.33 (m, 1H), 7.20 (s, 1H), 7.48 (td, J1 = 7.7 Hz, J2 =
1.4 Hz, 1H), 7.64 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 8.03 (d, J = 9.1 Hz,
1H), 8.05 (d, J = 9.3 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 26.1,
26.3, 26.6, 26.9, 32.8, 33.6, 38.9, 47.8, 115.7, 122.7, 125.1, 125.6,
128.5, 129.9, 148.0, 153.3, 166.6 ppm; HRMS (ESI) calcd for C21H28
N
[M + H]+ 294.2216, found 294.2203.
4-Cycloheptyl-6-methoxy-2-methylquinoline (2b-C): 468.7 mg,
87 % yield; yellow oil; IR (neat) 2921, 2853, 2361, 1561, 774 cm–1
;
6-Cyclopentylphenanthridine (2g-A): 445.2 mg, 90 % yield; yellow
1H NMR (400 MHz, CDCl3) δ 1.61–1.83 (m, 8H), 1.87–1.94 (m, 2H),
2.02–2.07 (m, 2H), 2.68 (s, 3H), 3.33 (tt, J1 = 11.0 Hz, J2 = 3.4 Hz, 1H),
3.95 (s, 3H), 7.13 (s, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.33 (dd, J1 = 9.1 Hz,
J2 = 2.7 Hz, 1H), 7.95 (d, J = 9.3 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 24.9, 27.4, 27.7, 35.3, 40.4, 55.3, 101.8, 118.6, 120.2, 125.5,
130.6, 143.8, 153.8, 156.0, 156.8 ppm; HRMS (ESI) calcd for C18H24ON
[M + H]+ 270.1852, found 270.1844.
1
oil; IR (neat) 3071, 2948, 2865, 1154, 905 cm–1; H NMR (400 MHz,
CDCl3) δ 1.72–1.84 (m, 2H), 1.88–1.98 (m, 2H), 2.12–2.30 (m, 4H),
4.08 (quin, J-= 8.2 Hz, 1H), 7.60 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H),
7.66–7.71 (m, 2H), 7.81 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 8.11 (dd,
J1 = 8.0 Hz, J2 = 1.4 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.53 (dd, J1 =
7.7 Hz, J2 = 1.4 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 26.0, 32.1, 43.5, 121.8, 122.4, 123.4, 125.6, 126.1,
126.2, 127.0, 128.3, 129.8,129.9, 132.9, 143.7, 164.1 ppm; HRMS (ESI)
calcd for C18H18N [M + H]+ 248.1434, found 248.1435.
4-Cyclooctyl-6-methoxy-2-methylquinoline (2b-D): 464.7 mg,
1
82 % yield; yellow oil; IR (neat) 2918, 2849, 1561, 680, 519 cm–1; H
NMR (400 MHz, CDCl3) δ 1.68–1.71 (m, 7H), 1.85–1.98 (m, 7H), 2.68
(s, 3H), 3.45 (tt, J1 = 8.8 Hz, J2 = 3.9 Hz, 1H), 3.95 (s, 3H), 7.13 (s, 1H),
7.28 (d, J = 2.7 Hz, 1H), 7.33 (dd, J1 = 9.1 Hz, J2 = 2.7 Hz, 1H), 7.95
(d, J = 9.3 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 24.9, 26.0,
26.4, 26.6, 33.0, 38.2, 55.2, 101.8, 118.9, 120.2, 125.4, 130.6, 143.8,
153.9, 155.8, 156.7 ppm; HRMS (ESI) calcd for C19H26ON [M + H]+
284.2009, found 284.1995.
6-Cyclohexylphenanthridine (2g-B): 465.2 mg, 89 % yield; yellow
1
oil; IR (neat) 3072, 2925, 2850, 1135, 556 cm–1; H NMR (400 MHz,
CDCl3) δ 1.37–1.48 (m, 1H), 1.51–1.63 (m, 2H), 1.83–1.89 (m, 1H),
1.92–1.99 (m, 4H), 2.05–2.09 (m, 2H), 3.62 (tt, J1 = 12.0 Hz, J2 =
3.4 Hz, 1H), 7.60 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 7.67–7.72 (m, 2H),
7.82 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 8.13 (dd, J1 = 7.7 Hz, J2 =
1.4 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.54 (dd, J1 = 7.7 Hz, J2 = 1.4 Hz,
1H), 8.66 (d, J = 8.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 26.3,
26.8, 32.3, 41.9, 121.8, 122.5, 123.3, 124.7, 125.5, 126.1, 127.0, 128.3,
4-Cyclododecyl-6-methoxy-2-methylquinoline (2b-E): 624.7 mg,
92 % yield; yellow soild, mp 134–135 °C; IR (neat) 2929, 1620, 1403,
1165, 569 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.22–1.30 (m, 2H), 1.40– 129.8, 129.9, 133.0, 143.8, 165.3 ppm; HRMS (ESI) calcd for C19H20
N
1.59 (m, 16H), 1.63–1.71 (m, 2H), 1.86–1.94 (m, 2H), 2.69 (s, 3H), 3.52 [M + H]+ 262.1590, found 262.1589.
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6-Cycloheptylphenanthridine (2g-C): 528.7 mg, 96 % yield; yellow
CDCl3) δ 1.61–1.80 (m, 6H), 1.88–2.01 (m, 6H), 3.73 (tt, J1 = 10.0 Hz,
J2 = 3.9 Hz, 1H), 7.47 (d, J = 5.9 Hz, 1H), 7.59 (td, J1 = 7.6 Hz, J2 =
1.4 Hz, 1H), 7.65 (td, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.81 (d, J = 7.9 Hz,
1H), 8.21 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 5.7 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 27.5, 28.0, 34.6, 43.2, 118.7, 124.8, 125.9, 126.8,
1
oil; IR (neat) 3071, 2920, 2852, 1166, 586 cm–1; H NMR (400 MHz,
CDCl3) δ 1.60–2.17 (m, 12H), 3.77 (tt, J1 = 11.0 Hz, J2 = 3.4 Hz, 1H),
7.59 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 7.66–7.71 (m, 2H), 7.80 (td, J1 =
7.6 Hz, J2 = 1.1 Hz, 1H), 8.11 (dd, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 8.28
(d, J = 8.0 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 8.0 Hz, 1H)
127.5, 129.5, 136.4, 141.8, 167.2 ppm; HRMS (ESI) calcd for C16H20
N
ppm; 13C NMR (100 MHz, CDCl3) δ 27.5, 28.2, 34.1, 47.5, 119.7, 121.8, [M + H]+ 226.1590, found 226.1586.
122.6, 123.3, 124.5, 125.7, 126.1, 127.0, 128.4, 129.8, 133.1, 143.7,
1-Cyclooctylisoquinoline (2h-D): 416.4 mg, 87 % yield; yellow oil;
IR (neat) 3049, 2917, 2848, 1141, 572 cm–1 1H NMR (400 MHz,
166.6 ppm; HRMS (ESI) calcd for C20H22N [M + H]+ 276.1747, found
276.1744.
;
CDCl3) δ 1.62–1.79 (m, 8H), 1.87–1.91 (m, 2H), 1.96–2.12 (m, 4H),
3.84 (tt, J1 = 5.4 Hz, J2 = 3.7 Hz, 1H), 7.47 (d, J = 5.9 Hz, 1H), 7.59
(td, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.65 (td, J1 = 7.6 Hz, J2 = 1.4 Hz,
1H), 7.81 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 8.46 (d, J =
5.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 26.2, 26.6, 26.7, 33.0,
40.9, 118.6, 124.1, 125.8, 126.7, 127.5, 129.4, 136.4, 141.7, 167.8 ppm;
HRMS (ESI) calcd for C17H22N [M + H]+ 240.1747, found 240.1733.
6-Cyclooctylphenanthridine (2g-D): 520.9 mg, 90 % yield; yellow
1
oil; IR (neat) 3071, 2917, 2848, 1204, 948 cm–1; H NMR (400 MHz,
CDCl3) δ 1.65–1.81 (m, 8H), 1.90–1.97 (m, 2H), 2.05–2.22 (m, 4H),
3.89 (tt, J1 = 12.0 Hz, J2 = 3.6 Hz, 1H), 7.60 (td, J1 = 7.6 Hz, J2 =
1.1 Hz, 1H), 7.67–7.72 (m, 2H), 7.82 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H),
8.12 (dd, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.54
(dd, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 8.66 (d, J = 8.0 Hz, 1H) ppm; 13C
NMR (100 MHz, CDCl3) δ 26.0, 26.3, 26.8, 26.8, 32.6, 121.7, 122.6,
123.2, 124.5, 125.8, 126.1, 127.0, 128.4, 129.8, 129.9, 133.2, 143.7,
167.2 ppm; HRMS (ESI) calcd for C21H24N [M + H]+ 290.1903, found
290.1902.
1-Cyclododecylisoquinoline (2h-E): 401.8 mg, 68 % yield; white
1
soild, mp 87–88 °C; IR (neat) 2928, 2860, 1585, 1008, 869 cm–1; H
NMR (400 MHz, CDCl3) δ 1.18–1.26 (m, 2H), 1.35–1.63 (m, 16H),
1.84–2.00 (m, 4H), 3.88 (quin, J = 6.0 Hz, 1H), 7.48 (d, J = 5.9 Hz,
1H), 7.61 (td, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.66 (td, J1 = 7.6 Hz, J2 =
1.4 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.50 (d,
J = 5.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 22.9, 23.5, 23.7,
23.8, 23.9, 29.7, 36.6, 118.8, 124.6, 126.9, 127.0, 127.5, 129.5, 136.3,
141.9, 165.7 ppm; HRMS (ESI) calcd for C21H30N [M + H]+ 296.2373,
found 296.2355.
6-Cyclododecylphenanthridine (2g-E): 456.0 mg, 66 % yield;
white soild, mp 116–117 °C; IR (neat) 2931, 2849, 1610, 1153,
1
930 cm–1; H NMR (400 MHz, CDCl3) δ 1.24–1.45 (m, 9H), 1.44–1.70
(m, 9H), 1.93–2.10 (m, 4H), 3.95 (quin, J = 6.0 Hz, 1H), 7.60 (td, J1 =
7.6 Hz, J2 = 1.1 Hz, 1H), 7.68–7.73 (m, 2H), 7.83 (td, J1 = 7.6 Hz, J2 =
1.1 Hz, 1H), 8.14 (dd, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 8.35 (d, J = 8.0 Hz,
1H), 8.55 (dd, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 8.67 (d, J = 8.0 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 23.3, 23.4, 23.8, 24.0, 29.4, 34.9,
36.9, 121.8, 122.6, 123.2, 125.4, 125.5, 126.0, 127.2, 128.3, 129.8,
129.9, 133.0, 143.8, 165.1 ppm; HRMS (ESI) calcd for C25H32N [M +
H]+ 346.2529, found 346.2520.
1-(Adamantan-1′-yl)isoquinoline (2h-F): 331.8 mg, 63 % yield;
white soild, mp 119–120 °C; IR (neat) 2903, 2850, 1498, 1363,
1
965 cm–1; H NMR (400 MHz, CDCl3) δ 1.60–2.54 (m, 15H), 7.47 (d,
J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.80
(d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 27.9, 28.4, 30.9, 32.6, 33.0, 36.2,
38.0, 40.0, 41.4, 47.5, 118.7, 125.3, 126.5, 127.7, 128.1, 129.1, 136.3,
141.2, 164.6 ppm; HRMS (ESI) calcd for C19H22N [M + H]+ 264.1747,
found 264.1744.
6-(Adamantan-1′-yl)phenanthridine (2g-F): 401.2 mg, 64 % yield;
white soild, mp 144–145 °C; IR (neat) 2898, 2845, 1525, 992,
580 cm–1; 1H NMR (400 MHz, CDCl3) δ 1.56–2.65 (m, 15H), 7.37–7.46
(m, 1H), 7.58–7.70 (m, 2H), 7.75–7.80 (m, 1H), 8.14 (ddd, J1 = 8.8 Hz,
J2 = 8.1 Hz, J3 = 1.1 Hz, 1H), 8.53 (ddd, J1 = 4.0 Hz, J2 = 3.3 Hz, J3 =
1.1 Hz, 1H), 8.67 (d, J = 8.1 Hz, 1H), 8.86 (d, J = 8.1 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 28.0, 28.5, 29.2, 32.6, 32.7, 37.2, 38.1,
40.1, 42.0, 43.0, 47.6, 121.6, 121.7, 122.6, 123.0, 125.7, 126.1, 126.4,
127.9, 128.2, 128.3, 129.1, 129.6, 130.2 ppm; HRMS (ESI) calcd for
C23H24N [M + H]+ 314.1903, found 314.1898.
4-Bromo-1-cyclohexylisoquinoline (2i-B): 545.5 mg, 94 % yield;
white soild, mp 99–100 °C; IR (neat) 2918, 2846, 1496, 1189,
1
851 cm–1; H NMR (400 MHz, CDCl3) δ 1.24–1.43 (m, 1H), 1.47–1.58
(m, 3H), 1.74–1.85 (m, 3H), 1.92–1.98 (m, 3H), 3.52 (tt, J1 = 11.8 Hz,
J2 = 2.9 Hz, 1H), 7.66 (td, J1 = 7.8 Hz, J2 = 1.1 Hz, 1H), 7.78 (td, J1 =
7.8 Hz, J2 = 1.1 Hz, 1H), 8.21 (dd, J1 = 10.2 Hz, J2 = 3.2 Hz, 2H), 8.66
(s, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 26.1, 26.8, 32.5, 41.4, 117.5,
125.1, 126.8, 127.6, 127.7, 130.8, 134.9, 143.6, 165.3 ppm; HRMS (ESI)
calcd for C15H17NBr [M + H]+ 290.0539, found 290.0535.
1-Cyclopentylisoquinoline (2h-A): 343.2 mg, 87 % yield; yellow oil;
IR (neat) 3050, 2948, 2866, 1146, 571 cm–1 1H NMR (400 MHz,
;
CDCl3) δ 1.72–1.84 (m, 2H), 1.87–1.96 (m, 2H), 2.04–2.19 (m, 4H),
4.03 (quin, J = 8.4 Hz, 1H), 7.48 (d, J = 5.9 Hz, 1H), 7.58 (td, J1 =
7.6 Hz, J2 = 1.4 Hz, 1H), 7.65 (td, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.80
(d, J = 7.9 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.46 (d, J = 5.7 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 25.6, 26.0, 32.7, 42.9, 118.9, 125.2,
126.7, 127.1, 127.3, 129.5, 136.2, 141.8, 164.7 ppm; HRMS (ESI) calcd
for C14H16N [M + H]+ 198.1277, found 198.1280.
2-Cyclopentylbenzothiazole (2j-A): 378.1 mg, 93 % yield; yellow
oil; IR (neat) 2953, 2868, 1312, 936, 517 cm–1 1H NMR (400 MHz,
;
CDCl3) δ 1.61–1.74 (m, 2H), 1.82–2.00 (m, 4H), 2.22–2.30 (m, 2H),
3.55 (quin, J = 8.2 Hz, 1H), 7.34 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 7.44
(td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 7.84 (dd, J1 = 7.9 Hz, J2 = 0.7 Hz,
1H), 7.96 (dd, J1 = 8.2 Hz, J2 = 0.5 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 25.5, 34.0, 44.7, 121.4, 122.4, 124.5, 125.8, 134.7, 153.1,
177.1 ppm; HRMS (ESI) calcd for C12H14NS [M + H]+ 204.0841, found
204.0835.
1-Cyclohexylisoquinoline (2h-B): 397.2 mg, 94 % yield; yellow oil;
IR (neat) 3050, 2924, 2850, 1266, 571 cm–1 1H NMR (400 MHz,
;
CDCl3) δ 1.33–1.59 (m, 3H), 1.78–1.88 (m, 3H), 1.91–2.01 (m, 4H),
3.56 (tt, J1 = 12.0 Hz, J2 = 3.4 Hz, 1H), 7.48 (d, J = 5.9 Hz, 1H), 7.58
(td, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.68 (td, J1 = 7.6 Hz, J2 = 1.4 Hz,
1H), 7.81 (d, J = 7.9 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.48 (d, J =
5.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 26.2, 26.8, 32.5, 41.4,
118.8, 124.6, 126.2, 126.7, 127.5, 129.4, 136.3, 141.8, 165.6 ppm;
HRMS (ESI) calcd for C15H18N [M + H]+ 212.1434, found 212.1434.
2-Cyclohexylbenzothiazole (2j-B): 417.2 mg, 96 % yield; yellow oil;
IR (neat) 2925, 2851, 1067, 847, 517 cm–1; 1H NMR (400 MHz, CDCl3)
δ 1.25–1.37 (m, 1H), 1.39–1.51 (m, 2H), 1.59–1.70 (m, 2H), 1.75–1.80
(m, 1H), 1.87–1.92 (m, 2H), 2.19–2.23 (m. 2H), 3.11 (tt, J1 = 12.0 Hz,
J2 = 3.4 Hz, 1H), 7.34 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 7.45 (td, J1 =
7.7 Hz, J2 = 1.4 Hz, 1H), 7.85 (dd, J1 = 7.9 Hz, J2 = 0.7 Hz, 1H), 7.97
(dd, J1 = 8.2 Hz, J2 = 0.5 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 25.7, 26.0, 33.4, 43.4, 121.5, 122.5, 124.4, 125.7, 134.5, 153.0,
1-Cycloheptylisoquinoline (2h-C): 423.6 mg, 94 % yield; yellow oil;
IR (neat) 3050, 2920, 2852, 1241, 951 cm–1 1H NMR (400 MHz,
;
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177.6 ppm; HRMS (ESI) calcd for C13H16NS [M + H]+ 218.0998, found
218.0989.
CHCl3 (3 × 20 mL). The resulting organic layer was dried with
Na2SO4, and filtered, and the solvent was removed under reduced
pressure. The residue was purified by column chromatography on
neutral silica gel (eluent: EtOAc/hexane, 1:5) to give product 4a-
B (149.5 mg, 67 %).
2-Cycloheptylbenzothiazole (2j-C): 425.7 mg, 92 % yield; yellow
1
oil; IR (neat) 2923, 2853, 1065, 1014, 935 cm–1; H NMR (400 MHz,
CDCl3) δ 1.59–1.72 (m, 6H), 1.83–1.92 (m, 4H), 2.20–2.26 (m, 2H),
3.30 (tt, J1 = 10.0 Hz, J2 = 3.9 Hz, 1H), 7.33 (td, J1 = 7.6 Hz, J2 =
2-(Cyclohexen-1′-yl)-4-methylquinoline (4a-B): 149.5 mg, 67 %
1.1 Hz, 1H), 7.44 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 7.84 (dd, J1 = yield; yellow oil; IR (neat) 2926, 1388, 1233, 919, 799 cm–1; H NMR
1
7.9 Hz, J2 = 0.7 Hz, 1H), 7.96 (dd, J1 = 8.2 Hz, J2 = 0.5 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 26.5, 28.0, 35.3, 45.5, 121.5, 122.5,
124.4, 125.7, 134.6, 152.9, 178.7 ppm; HRMS (ESI) calcd for C14H18NS
[M + H]+ 232.1154, found 232.1147.
(400 MHz, CDCl3) δ 1.70–1.75 (m, 2H), 1.81–1.87 (m, 2H), 2.29–2.34
(m, 2H), 2.66–2.71 (m, 2H), 2.68 (s, 3H), 6.75 (tt, J1 = 4.0 Hz, J2 =
1.8 Hz, 1H), 7.41 (s, 1H), 7.48 (td, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.65
(td, J1 = 7.6 Hz, J2 = 1.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 8.05 (d, J =
8.5 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 18.8, 22.1, 22.8, 25.9,
26.0, 118.6, 123.4, 125.3, 127.0, 128.8, 129.8, 129.9, 137.6, 143.5,
147.5, 158.9 ppm; HRMS (ESI) calcd for C16H18N [M + H]+ 224.1434,
found 224.1427.
2-Cyclooctylbenzothiazole (2j-D): 436.8 mg, 89 % yield; yellow oil;
IR (neat) 2919, 2850, 1697, 933, 875 cm–1; 1H NMR (400 MHz, CDCl3)
δ 1.61–1.67 (m, 8H), 1.81–1.83 (m, 2H), 1.92–2.01 (m, 2H), 2.12–2.20
(m, 2H), 3.38 (tt, J1 = 9.6 Hz, J2 = 3.9 Hz, 1H), 7.33 (td, J1 = 7.6 Hz,
J2 = 1.1 Hz, 1H), 7.44 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 7.84 (dd, J1 =
7.9 Hz, J2 = 0.7 Hz, 1H), 7.97 (dd, J1 = 8.2 Hz, J2 = 0.5 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 25.4, 26.1, 26.8, 32.9, 43.6, 121.5, 122.5,
124.5, 125.7, 134.6, 152.9, 179.2 ppm; HRMS (ESI) calcd for C15H20NS
[M + H]+ 246.1311, found 246.1303.
6-(Cyclohexen-1′-yl)phenanthridine (4g-B): 160.8 mg, 62 % yield;
white oil; IR (neat) 2926, 2363, 1406, 1165, 982 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 1.83–1.97 (m, 4H), 2.32–2.36 (m, 2H), 2.52–2.60
(m, 2H), 6.03 (tt, J1 = 3.9 Hz, J2 = 1.8 Hz, 1H), 7.63 (td, J1 = 7.5 Hz,
J2 = 1.4 Hz, 1H), 7.65 (td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 7.72 (td, J1 =
7.6 Hz, J2 = 1.6 Hz, 1H), 7.84 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 8.19
(dd, J1 = 8.2 Hz, J2 = 0.9 Hz, 1H), 8.28 (dd, J1 = 8.2 Hz, J2 = 0.7 Hz,
1H), 8.57 (dd, J1 = 8.2 Hz, J2 = 1.4 Hz, 1H), 8.65 (d, J = 8.4 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 22.0, 22.8, 25.3, 29.1, 121.8, 122.1,
123.6, 124.9, 126.5, 126.9, 128.4, 128.6, 129.6, 130.0, 130.4, 133.3,
137.5, 143.7, 163.7 ppm; HRMS (ESI) calcd for C19H18N [M + H]+
260.1434, found 260.1426.
2-Cyclododecylbenzothiazole (2j-E): 403.9 mg, 67 % yield; yellow
1
soild, mp 32–33 °C; IR (neat) 2925, 2859, 1064, 1027, 964 cm–1; H
NMR (400 MHz, CDCl3) δ 1.30–1.65 (m, 18H), 1.75–1.84 (m, 2H),
1.91–1.98 (m, 2H), 3.37 (tt, J1 = 9.7 Hz, J2 = 6.8 Hz, 1H), 7.34 (td, J1 =
7.6 Hz, J2 = 1.1 Hz, 1H), 7.44 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H), 7.84
(dd, J1 = 7.9 Hz, J2 = 0.7 Hz, 1H), 7.99 (dd, J1 = 8.2 Hz, J2 = 0.5 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 22.6, 23.3, 23.5, 23.6, 23.7,
30.9, 40.0, 121.4, 122.5, 124.4, 125.7, 134.7, 153.0, 178.1 ppm; HRMS
(ESI) calcd for C19H28NS [M + H]+ 302.1937, found 302.1924.
1-(Cyclohexen-1′-yl)isoquinoline (4h-B): 133.9 mg, 64 % yield; yel-
low oil; IR (neat) 2932, 1620, 1583, 1497, 1108 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 1.78–1.93 (m, 4H), 2.29–2.34 (m, 2H), 2.53–2.57
(m, 2H), 5.96 (tt, J1 = 3.6 Hz, J2 = 1.8 Hz, 1H), 7.52–7.56 (m, 2H), 7.68
(td, J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 8.23 (d, J =
8.6 Hz, 1H), 8.48 (d, J = 5.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 22.1, 22.9, 25.4, 29.0, 119.2, 126.4, 126.6, 126.8, 127.4, 129.8, 130.2,
136.8, 136.9, 141.8, 163.4 ppm; HRMS (ESI) calcd for C15H16N [M +
H]+ 210.1277, found 210.1272.
2-(Adamantan-1′-yl)benzothiazole (2j-F): 463.3 mg, 86 % yield;
yellow soild, mp 68–69 °C; IR (neat) 2846, 2359, 1342, 1073,
1
876 cm–1; H NMR (400 MHz, CDCl3) δ 1.59–1.60 (m, 1H), 1.69–1.91
(m, 1H), 1.81–1.84 (m, 5H), 1.96–2.06 (m, 2H), 2.13– (m, 6H), 7.34 (td,
J1 = 7.6 Hz, J2 = 1.1 Hz, 1H), 7.44 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1H),
7.84 (dd, J1 = 7.9 Hz, J2 = 0.7 Hz, 1H), 7.99 (dd, J1 = 8.2 Hz, J2 =
0.5 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 27.5, 27.8, 28.5, 32.5,
32.6, 36.5, 37.5, 38.5, 40.1, 43.0, 121.4, 121.5, 122.6, 124.4, 124.5,
Typical Procedure for Transformation of Compounds 4 to Com-
125.7, 153.1 ppm; HRMS (ESI) calcd for C17H20NS [M + H]+ 270.1311, pounds 5; Preparation of 4-Methyl-2-phenylquinoline (5a-B):
found 270.1306.
SeO2 (3.0 mmol, 332.9 mg) was added to a solution of 2-(cyclo-
hexen-1′-yl)-4-methylquinoline (4a-B; 1.0 mmol, 223.3 mg) in DCE
(3.0 mL) in a screw-capped flask (50 mL) at room temperature. The
mixture was flashed with argon gas and was stirred for 12 h at
80 °C. The reaction mixture was cooled to room temperature, and
the solvent was removed under reduced pressure. Then, the resid-
ual mixture was filtered and washed with CHCl3 (3 × 20 mL). After
the evaporation of the filtrate, the residue was purified by column
chromatography on neutral silica gel (eluent: EtOAc/hexane, 1:4) to
give product 5a-B (116.2 mg, 53 %).
Typical Procedure for Transformation of Compounds 2 to Com-
pounds 3; Preparation of 2-(1′-Bromocyclohexyl)-4-methylquinoline
(3a-B): NBS (1.5 mmol, 267.0 mg) was added to a solution of 2-
cyclohexyl-4-methylquinoline (2a-B; 1.0 mmol, 225.3 mg) in carbon
tetrachloride (4.0 mL) in a screw-capped flask (30 mL) at room tem-
perature. The reaction mixture was flashed with argon gas. The mix-
ture was stirred for 4 h under irradiation with a tungsten lamp
(300 W) at the range of 35–40 °C. Then, the reaction mixture was
quenched with satd. aq. Na2SO3 (10 mL), and the mixture was ex-
tracted with CHCl3 (3 × 20 mL). The resulting organic layer was
4-Methyl-2-phenylquinoline (5a-B): Yield: 116.2 mg (53 %); yellow
dried with Na2SO4, and filtered, and the solvent was removed under oil; IR (neat) 2923, 1509, 1281, 1238, 902 cm–1; 1H NMR (400 MHz,
reduced pressure. The residue was purified by column chromatogra- CDCl3) δ 2.78 (s, 3H), 7.46 (tt, J1 = 7.4 Hz, J2 = 2.5 Hz, 1H), 7.51–7.57
phy on neutral silica gel (eluent: EtOAc/hexane, 1:30) to give prod- (m, 3H), 7.70–7.75 (m, 2H), 8.01 (d, J = 7.4 Hz, 1H), 8.14–8.19 (m, 3H)
uct 3a-B (251.5 mg, 83 %).
ppm; 13C NMR (100 MHz, CDCl3) δ 19.0, 119.8, 123.6, 126.0, 127.2,
127.5, 128.8, 129.2, 129.3, 130.3, 139.8, 144.8, 148.1, 157.1 ppm;
HRMS (ESI) Calcd for C16H14N [M + H]+ 220.1121, found 220.1115.
Typical Procedure for Transformation of Compounds 3 to Com-
pounds 4; Preparation of 2-(Cyclohexen-1′-yl)-4-methylquinoline
(4a-B): tBuOK (3.0 mmol, 336.7 mg) was added to a solution of 2-
(1′-bromocyclohexyl)-4-methylquinoline (3a-B; 1.0 mmol, 304.2 mg)
in THF (2.0 mL) in a screw-capped flask (50 mL) at room tempera-
ture. The mixture was flashed with argon gas, and was stirred for
24 h at room temperature. Then, the reaction mixture was
quenched with satd. aq. NaCl (10 mL) and was extracted with
6-Phenylphenanthridine (5g-B): Yield: 122.5 mg (48 %); pink solid;
mp: 99–101 °C; IR (neat) 1360, 1137, 960, 758, 695 cm–1; 1H NMR
(400 MHz, CDCl3) δ 7.51–7.64 (m, 4H), 7.68–7.79 (m, 4H), 7.87 (t, J =
7.2 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.25 (dd, J1 = 8.1 Hz, J2 = 1.4 Hz,
1H), 8.63 (d, J = 8.1 Hz, 1H), 8.72 (d, J = 8.3 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 121.9, 122.1, 123.7, 125.2, 126.9, 127.1, 128.4,
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1-Phenylisoquinoline (5h-B): Yield: 86.2 mg (42 %); red solid; mp:
93–94 °C; IR (neat) 3053, 2849, 1618, 1441, 1319 cm–1 1H NMR
;
(400 MHz, CDCl3) δ 7.48–7.57 (m, 4H), 7.66 (dd, J1 = 6.0 Hz, J2 =
0.7 Hz, 1H), 7.68–7.72 (m, 3H), 7.90 (d, J = 8.2 Hz, 1H), 8.11 (dd, J1 =
8.6 Hz, J2 = 0.9 Hz, 1H), 8.62 (d, J = 5.7 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 119.9, 126.7, 127.0, 127.1, 127.6, 128.3, 128.6,
129.9, 130.0, 136.8, 139.6, 142.2, 160.7; HRMS (ESI) Calcd for C15H12
N
[M + H]+ 206.0970, found 206.0966.
Supporting Information: (see footnote on the first page of this
1
article): Copies of the H NMR and 13C NMR spectra of all products
2a-A–2j-F, 4a-B, 4g-B, 4h-B, 5a-B, 5g-B, and 5h-B.
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Acknowledgments
Financial support in the form of a Grant-in–Aid for Scientific
Research (No. 15K05418) from the Ministry of Education, Cul-
ture, Sports, Science, and Technology in Japan is gratefully ac-
knowledged.
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Keywords: Heterocycles · Cycloalkanes · Radicals ·
Alkylation · BPO
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Received: December 9, 2018
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Full Paper
Heteroaromatic Bases
L. Zhou, H. Togo* ............................... 1–9
Introduction of Heteroaromatic
Bases onto Cycloalkanes with BPO
Treatment of heteroaromatics with heteroaromatic bases bearing cyclo-
BPO and CF3CO2H in cycloalkanes at aklyl group in good yields under tran-
100 °C for 4 h generated C–C bonded sition-metal-free conditions.
DOI: 10.1002/ejoc.201801797
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